Hepatitis B antiviral agents

ABSTRACT

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, thereof: 
                         
which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/617,445, filed on Jun. 8, 2017, which claims the benefit of U.S.Provisional Application No. 62/348,419, filed on Jun. 10, 2016, and62/443,245, filed on Jan. 6, 2017. The entire teachings of the aboveapplications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to novel antiviral agents.Specifically, the present invention relates to compounds which caninhibit the protein(s) encoded by hepatitis B virus (HBV) or interferewith the function of the HBV life cycle, compositions comprising suchcompounds, methods for inhibiting HBV viral replication, methods fortreating or preventing HBV infection, and processes for making thecompounds.

BACKGROUND OF THE INVENTION

HBV infection remains a major public health problem, affectingapproximately 2 billion people worldwide. Among them, 350 million peopleworldwide and 1.4 million in the US develop a chronic infection, whichcan lead to chronic persistent hepatitis, liver cirrhosis, andhepatocellular carcinoma (HCC). Every year 500,000 to 1 million peopledie from the end stage of liver diseases caused by HBV infection.

Despite the availability of a prophylactic HBV vaccine, the burden ofchronic HBV infection continues to be a significant unmet worldwidemedical problem, due to suboptimal treatment options and sustained ratesof new infections in most parts of the developing world. Currenttreatments do not provide a cure and are limited to only two classes ofagents (interferon and nucleoside analogues/inhibitors of the viralpolymerase); drug resistance, low efficacy, and tolerability issueslimit their impact. The low cure rates of HBV are attributed at least inpart to the presence and persistence of covalently closed circular DNA(cccDNA) in the nucleus of infected hepatocytes. However, persistentsuppression of HBV DNA slows liver disease progression and helps toprevent HCC. Current therapy goals for HBV-infected patients aredirected to reducing serum HBV DNA to low or undetectable levels, and toultimately reducing or preventing the development of cirrhosis and HCC.

The HBV is an enveloped, partially double-stranded DNA (dsDNA) virus ofthe hepadnavirus family (Hepadnaviridae). HBV capsid protein (CP) playsessential roles in HBV replication. The predominant biological functionof capsid protein is to act as a structural protein to encapsidatepre-genomic RNA and form immature capsid particles, which spontaneouslyself-assemble from many copies of core dimers in the cytoplasm. Capsidprotein also regulates viral DNA synthesis through differentphosphorylation status of its C-terminal phosphorylation sites. Also,capsid protein might facilitate the nuclear translocation of viralrelaxed circular genome by means of the nuclear localization signalslocated in the Arginine-rich domain of the C-terminal region of capsidprotein. In the nucleus, as a component of viral cccDNA minichromosome,capsid protein could play a structural and regulatory role in thefunctionality of cccDNA minichromosomes. Capsid protein also interactswith viral large envelope protein in endoplasmic reticulum (ER) andtriggers the release of intact viral particles from hepatocytes.

Capsid related anti-HBV inhibitors have been reported. For example,phenylpropen-amide derivatives, including compounds named AT-61 andAT-130 (Feld J. et al. Antiviral Res. 2007, 76, 168), and a class ofthiazolidin-4-ones from Valeant (WO2006/033995), have been shown toinhibit pregenomic RNA (pgRNA) packaging. Heteroaryldihydropyrimi-dinesor HAPs were discovered in a tissue culture-based screening (Weber etal., Antiviral Res. 2002, 54, 69). These HAP analogs act as syntheticallosteric activators and are able to induce aberrant capsid formationthat leads to degradation of the core protein. A subclass ofsulphamoyl-arylamides also shows activity against HBV (WO 2013/006394,WO 2013/096744, and WO 2014184365). It was also shown that the smallmolecule bis-ANS acts as a molecular ‘wedge’ and interferes with normalcapsid-protein geometry and capsid formation (Zlotnick A. et al. J.Virol. 2002, 4848).

There is a need in the art for novel therapeutic agents that treat,ameliorate or prevent HBV infection. Administration of these therapeuticagents to an HBV infected patient, either as monotherapy or incombination with other HBV treatments or ancillary treatments, will leadto significantly improved prognosis, diminished progression of thedisease, and enhanced seroconversion rates.

SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds,pharmaceutical compositions comprising such compounds, as well asmethods to treat or prevent viral (particularly HBV) infection in asubject in need of such therapy with said compounds. Compounds of thepresent invention inhibit the protein(s) encoded by hepatitis B virus(HBV) or interfere with the life cycle of HBV and are also useful asantiviral agents. In addition, the present invention includes theprocess for the preparation of the said compounds.

In its principal aspect, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted aryl or optionally substituted heteroaryl;preferably A is optionally substituted azolyl, optionally substitutedpyridyl, or optionally substituted phenyl;

B is selected from the group consisting of hydrogen, halo, CN,optionally substituted —C₁-C₆ alkyl, and optionally substituted —C₃-C₆cycloalkyl; preferably B is hydrogen or optionally substituted methyl;

X is optionally substituted aryl or optionally substituted heteroaryl;preferably X is optionally substituted phenyl;

Alternatively, B and X are taken together with the carbon atom to whichthey are attached to form an optionally substituted C₄-C₁₂ cycloalkenylor optionally substituted 4- to 12-membered heterocyclic, for example, aC₄-C₁₂ cycloalkenyl or 4- to 12-membered heterocyclic which is fusedwith an aryl or heteroaryl ring wherein each ring is optionally furthersubstituted;

Y is optionally substituted aryl or optionally substituted heteroaryl;preferably Y is optionally substituted azolyl, optionally substitutedpyridyl, or optionally substituted phenyl;

Z is selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —C₃-C₈cycloalkyl, optionally substituted 3- to 8-membered heterocyclic,optionally substituted aryl, optionally substituted heteroaryl,—C(O)NR₁R₂, and —C(O)OR₁;

R₁ and R₂ at each occurrence are independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₈ alkyl, optionallysubstituted —C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl,optionally substituted —C₃-C₈ cycloalkyl, optionally substituted 3- to8-membered heterocyclic, optionally substituted aryl and optionallysubstituted heteroaryl;

Alternatively, R₁ and R₂ are taken together with the nitrogen atom towhich they are attached form an optionally substituted 3- to 12-memberedheterocyclic;

R is selected from the group consisting of optionally substituted —C₁-C₈alkyl, optionally substituted —C₂-C₈ alkenyl, and optionally substituted—C₂-C₈ alkynyl;

Alternatively, R and Z are taken together with the atoms to which theyare attached to form an optionally substituted 4- to 12-memberedheterocyclic; and

Alternatively, R and A are taken together with the atoms to which theyare attached to form an optionally substituted 5- to 7-memberedheterocyclic.

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention is a compound of Formula (I)as described above, or a pharmaceutically acceptable salt thereof.

Compounds of Formula I can have the stereochemistry shown in Formula Iaor Formula Ib.

In preferred embodiments, compounds of Formula I have thestereochemistry shown in Formula Ia.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein A isan optionally substituted azolyl, optionally substituted pyridyl, oroptionally substituted phenyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Z ishydrogen, optionally substituted —C₁-C₄ alkyl, or optionally substituted—C₃-C₈ cycloalkyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Z isan optionally substituted methyl; preferably, Z is a methyl optionallysubstituted with halo, —OR₁₁, or —NR₁₁R₁₂; wherein R₁₁ and R₁₂ at eachoccurrence are independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₈ alkyl, optionally substituted—C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl, optionallysubstituted —C₃-C₈ cycloalkyl, optionally substituted 3- to 8-memberedheterocyclic, optionally substituted aryl and optionally substitutedheteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Z is—C(O)NR₁R₂ or —C(O)OR₁.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Z isoptionally substituted —C₂-C₈ alkenyl, or optionally substituted —C₂-C₈alkynyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Z isoptionally substituted 3- to 8-membered heterocyclic.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Z isselected from the groups set forth below:

wherein each of the above shown groups is optionally substituted. Thepreferred substituents include optionally substituted methyl, halo, —CN,═O, ═NR₁₁, —OR₁₁, and —NR₁₁R₁₂; wherein R₁₁ and R₁₂ are as previouslydefined.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Z is—(CH₂)_(n)OR₁₁, —(CH₂)_(n)OC(O)R₁₁, —(CH₂)_(n)C(O)OR₁₁,—(CH₂)_(n)C(O)NR₁₁R₁₂, —(CH₂)_(n)OC(O)OR₁₁, —(CH₂)_(n)O—C(O)NR₁₁R₁₂,—(CH₂)_(n)NR₁₁R₁₂, —(CH₂)_(n)NR₁₁C(O)R₁₁, —(CH₂)_(n)NR₁₁C(O)OR₁₁,—(CH₂)_(n)NR₁₁C(O)—NR₁₁R₁₂, —(CH₂)_(n)S(O)R₁₂, —(CH₂)_(n)OS(O)₂R₁₂,—(CH₂)_(n)S(O)₂OR₁₁, —(CH₂)_(n)NR₁₁S(O)₂R₁₂, —(CH₂)_(n)—S(O)₂NR₁₁R₁₂;—(CH₂)_(n)NR₁₁S(O)₂NR₁₁R₁₂; —(CH₂)_(n)OP(O)(OR₁₁)₂,—(CH₂)_(n)P(O)(OR₁₁)₂, —(CH₂)_(n)—NR₁₁P(O)(OR₁₂)₂, or—(CH₂)_(n)P(O)(NR₁₁R₁₂)₂; wherein n is 1, 2, 3, 4, 5, or 6; R₁₁ and R₁₂are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein B ishydrogen.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein B ishalo, preferably fluoro.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein B ismethyl, optionally substituted with one or more halo, preferably fluoro.In certain embodiments, B is difluoromethyl or trifluoromethyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted —C₁-C₆ alkyl. In certain embodiments, the presentinvention relates to compounds of Formula (I), and pharmaceuticallyacceptable salts thereof, wherein R is optionally substituted —C₃-C₈cycloalkyl.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein R isselected from methyl, ethyl, difluoromethyl, trifluoromethyl,—CH₂CH₂OR₁₁, —CH₂CH₂NR₁₁R₁₂, —CH₂C(O)R₁₁, and —CH₂C(O)NR₁₁R₁₂.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R is—(CH₂)_(n)OR₁₁, —(CH₂)_(n)OC(O)R₁₁, —(CH₂)_(n)C(O)OR₁₁,—(CH₂)_(n)C(O)NR₁₁R₁₂, —(CH₂)_(n)OC(O)OR₁₁, —(CH₂)_(n)O—C(O)NR₁₁R₁₂,—(CH₂)_(n)NR₁₁R₁₂, —(CH₂)_(n)NR₁₁C(O)R₁₁, —(CH₂)_(n)NR₁₁C(O)OR₁₁,—(CH₂)_(n)NR₁₁C(O)NR₁₁R₁₂, —(CH₂)_(n)S(O)R₁₂, —(CH₂)_(n)OS(O)₂R₁₂,—(CH₂)_(n)S(O)₂OR₁₁, —(CH₂)_(n)NR₁₁S(O)₂R₁₂, —(CH₂)_(n)S(O)₂—NR₁₁R₁₂;—(CH₂)_(n)NR₁₁S(O)₂NR₁₁R₁₂; —(CH₂)_(n)OP(O)(OR₁₁)₂,—(CH₂)_(n)P(O)(OR₁₁)₂, —(CH₂)_(n)NR₁₁P(O)(OR₁₂)₂, or—(CH₂)_(n)P(O)(NR₁₁R₁₂)₂; wherein n, R₁₁ and R₁₂ are as previouslydefined.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted phenyl. In certain embodiments, the presentinvention relates to compounds of Formula (I), and pharmaceuticallyacceptable salts thereof, wherein X is optionally substitutedheteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein A isoptionally substituted thiophenyl, optionally substituted imidazolyl,optionally substituted thiazolyl, optionally substituted oxazolyl,optionally substituted pyridyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Y isoptionally substituted phenyl. In certain embodiments, the presentinvention relates to compounds of Formula (I), and pharmaceuticallyacceptable salts thereof, wherein Y is optionally substitutedheteroaryl. In certain embodiments, the present invention relates tocompounds of Formula (I), and pharmaceutically acceptable salts thereof,wherein Y is optionally substituted azolyl or optionally substitutedpyridyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted phenyl; and Y is an optionally substitutedheteroaryl. In certain embodiments, the present invention relates tocompounds of Formula (I), and pharmaceutically acceptable salts thereof,wherein X is optionally substituted phenyl; and Y is optionallysubstituted azolyl, optionally substituted pyridyl, or optionallysubstituted phenyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted monocyclic heteroaryl; and Y is optionallysubstituted azolyl, optionally substituted pyridyl, or optionallysubstituted phenyl.

In another particular embodiment, the present invention relates tocompounds of Formula (I), or a pharmaceutically acceptable salt thereof,wherein A and X are each independently an aryl or heteroaryl groupderived from one of the following by removal of one hydrogen atom:

wherein each of the above shown aryl and heteroaryl groups is optionallysubstituted and is preferably connected to the dihydropyrimidine corethrough a carbon atom.

In another particular embodiment, the present invention relates tocompounds of Formula (I), or a pharmaceutically acceptable salt thereof,wherein at least one of A and X is an aryl or heteroaryl group derivedfrom one of the following by removal of one hydrogen atom:

wherein each of the above shown aryl and heteroaryl groups is optionallysubstituted and is preferably connected to the dihydropyrimidine corethrough a carbon atom.

In certain embodiments, A and X are each independently selected from thegroups set forth below:

wherein each of the above shown groups is optionally substituted. Thepreferred substituents are optionally substituted methyl, halo, CN,OR₁₁, and —NR₁₁R₁₂; wherein R and R₁₂ are as previously defined.

In certain embodiments, at least one of A and X is selected from thegroups set forth below:

wherein each of the above shown groups is optionally substituted whenpossible. The preferred substituents are optionally substituted methyl,halo, CN, OR₁₁, or —NR₁₁R₁₂; wherein R₁₁ and R₁₂ are as previouslydefined.

In certain embodiments, the present invention related to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Y isselected from the groups set forth below:

wherein each of the above shown groups is optionally substituted. Thepreferred substituents include optionally substituted methyl, halo, —CN,—OR₁₁, and —NR₁₁R₁₂; wherein R₁₁ and R₁₂ are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Y isoptionally substituted azolyl.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Y isselected from the groups set forth below:

wherein each of the above shown groups is optionally substituted whenpossible.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Y isselected from the groups set forth below:

wherein each of the above shown groups is optionally substituted. Thepreferred substituents include optionally substituted —C₁-C₄-alkyl,halo, —CN, —OR₁₁, and —NR₁₁R₁₂; R₁₁ and R₁₂ are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Y isselected from the groups set forth below:

wherein R₂₀ is optionally substituted C₁-C₄-alkyl or C₃-C₆-cycloalkyl.Preferably, R₂₀ is optionally substituted methyl or optionallysubstituted cyclopropyl.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Z is—(CH₂)_(n′)-M; wherein n′ is 1, 2, or 3; M is hydrogen, —OR₁₁, protectedhydroxy, —CR₁₁R₁₂R₃, —NR₁₁R₁₂, protected amino or selected from thegroups set forth below:

wherein each of the above shown groups is optionally substituted; thepreferred substituents include halo, ═O, ═NR₁₁, —OR₁₁, —NR₁₁R₁₂, —CN,—CO₂R₁₁, —C(O)NR₁₁R₁₂, and optionally substituted methyl; R₃ is selectedfrom the group consisting of hydrogen, optionally substituted —C₁-C₈alkyl, optionally substituted —C₂-C₈ alkenyl, optionally substituted—C₂-C₈ alkynyl, optionally substituted —C₃-C₈ cycloalkyl, —CN, —OR₁₁,and —NR₁₁R₁₂; R₄ is selected from the group consisting of —NR₁₁R₁₂,OR₁₁, optionally substituted —C₁-C₈ alkyl, optionally substituted —C₂-C₈alkenyl, optionally substituted —C₂-C₈ alkynyl, optionally substituted—C₃-C₈ cycloalkyl, optionally substituted 3- to 8-membered heterocyclic,optionally substituted aryl and optionally substituted heteroaryl; R₅ isselected from the group consisting of hydrogen, optionally substituted—C₁-C₈ alkyl, optionally substituted —C₂-C₈ alkenyl, optionallysubstituted —C₂-C₈ alkynyl, optionally substituted —C₃-C₈ cycloalkyl,optionally substituted 3- to 8-membered heterocyclic, optionallysubstituted aryl, optionally substituted heteroaryl, —C(O)R₁₁,—C(O)OR₁₁, —C(O)NR₁₁R₁₂, —S(O)₂R₁₁, —S(O)₂NR₁₁R₁₂; G is independentlyselected from CR₁₁R₁₂, O and NR₅; G′ is independently selected from CR₅and N; and n′, R₁ and R₁₂ are as previously defined. In certainembodiments, R₅ is selected from the groups set forth below:

wherein each of the above shown groups is optionally substituted; thepreferred substituents include halo, —OR₁₁, —NR₁₁R₁₂, —CN, —CO₂R₁,—C(O)NR₁₁R₁₂, optionally substituted methyl, and optionally substitutedphenyl. In another embodiment, R₅ is —SO₂NH₂.

In another embodiment, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein Z is—(CH₂)_(n′)-M, preferably —CH₂-M, wherein M is selected from the groupsset forth below:

wherein each of the above shown groups is optionally substituted whenpossible; the preferred substituents include halo, —OR₁₁, —NR₁₁R₁₂, —CN,—CO₂R₁, —C(O)NR₁₁R₁₂, optionally substituted methyl, and optionallysubstituted phenyl; m′ is 1, 2, or 3; and n′, R₁₁, R₁₂, and R₅ are aspreviously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof:

wherein A₁ is a 5-membered heteroaryl group containing 1 to 4heteroatoms selected from O, N, and S; preferably A₁ is an optionallysubstituted azole group including but not limited to pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl; each optionally substituted; A₂ is an optionallysubstituted phenyl, thiophenyl or 6-membered heteroaryl group includingbut not limited to pyridinyl, pyrazinyl, or pyrimidinyl; each optionallysubstituted; B, R, X, Y, and Z are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIa-1) or (IIb-1), or a pharmaceutically acceptable saltthereof:

wherein X₁ is optionally substituted methyl, halo, CN, OR₁₁, or NR₁₁R₁₂;m is 0, 1, 2, 3, 4 or 5; A₁, A₂, R, Y, Z, R₁₁, and R₁₂ are as previouslydefined.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIa-1) or (IIb-1), or a pharmaceutically acceptable saltthereof, wherein m is 0 or m is 1-5 and each X₁ is halo. In certainembodiments, the compound of Formula (I) is represented by Formula(IIa-1) or (IIb-1), or a pharmaceutically acceptable salt thereof,wherein Y is optionally substituted azolyl. In another embodiment, thecompound of Formula (I) is represented by Formula (IIa-1) or (IIb-1), ora pharmaceutically acceptable salt thereof, wherein Z is hydrogen oroptionally substituted methyl.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIa-1) or (IIb-1), or a pharmaceutically acceptable saltthereof, wherein R is selected from the group consisting of—(CH₂)_(n)OR₁₁, —(CH₂)_(n)OC(O)R₁₁, —(CH₂)_(n)C(O)OR₁₁,—(CH₂)_(n)C(O)NR₁₁R₁₂, —(CH₂)_(n)OC(O)OR₁₁, —(CH₂)_(n)O—C(O)NR₁₁R₁₂,—(CH₂)_(n)NR₁₁R₁₂, —(CH₂)_(n)NR₁₁C(O)R₁₁, —(CH₂)_(n)NR₁₁C(O)OR₁₁,—(CH₂)_(n)NR₁₁C(O)NR₁₁R₁₂, —(CH₂)_(n)S(O)R₁₂, —(CH₂)_(n)OS(O)₂R₁₂,—(CH₂)_(n)S(O)₂OR₁₁, —(CH₂)_(n)NR₁₁S(O)₂R₁₂, —(CH₂)_(n)S(O)₂NR₁₁R₁₂;—(CH₂)_(n)NR₁₁S(O)₂NR₁₁R₁₂; —(CH₂)_(n)OP(O)(OR₁₁)₂,—(CH₂)_(n)P(O)(OR₁₁)₂, —(CH₂)_(n)NR₁₁P(O)—(OR₁₂)₂, and—(CH₂)_(n)P(O)(NR₁₁R₁₂)₂; preferably, R is —(CH₂)_(n)OR₁₁; and n, R₁₁and R₁₂ are as previously defined.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIa-1) or (IIb-1), or a pharmaceutically acceptable saltthereof, wherein Z is selected from the group consisting of—(CH₂)_(n)OR₁₁, —(CH₂)_(n)OC(O)R₁₁, —(CH₂)_(n)C(O)OR₁₁,—(CH₂)_(n)C(O)NR₁₁R₁₂; —(CH₂)_(n)OC(O)OR₁₁, —(CH₂)_(n)O—C(O)NR₁₁R₁₂,—(CH₂)_(n)NR₁₁R₁₂, —(CH₂)_(n)NR₁₁C(O)R₁₁, —(CH₂)_(n)NR₁₁C(O)OR₁₁,—(CH₂)_(n)NR₁₁C(O)NR₁₁R₁₂, —(CH₂)_(n)S(O)R₁₂, —(CH₂)_(n)OS(O)₂R₁₂,—(CH₂)_(n)S(O)₂OR₁₁, —(CH₂)_(n)NR₁₁S(O)₂R₁₂, —(CH₂)_(n)S(O)₂NR₁₁R₁₂;—(CH₂)_(n)NR₁₁S(O)₂NR₁₁R₁₂; —(CH₂)_(n)OP(O)(OR₁₁)₂,—(CH₂)_(n)P(O)(OR₁₁)₂, —(CH₂)_(n)NR₁₁P(O)—(OR₁₂)₂, and—(CH₂)_(n)P(O)(NR₁₁R₁₂)₂; preferably, Z is —(CH₂)_(n)NR₁₁S(O)₂R₁₂; andn, R₁₁ and R₁₂ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIa-2), or (IIb-2), or a pharmaceutically acceptable saltthereof:

wherein X₁, m, A₁, A₂, R, Y, M, R₃, R₁₁ and R₁₂ are as previouslydefined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIa-2) or (IIb-2), or a pharmaceutically acceptable saltthereof, wherein M is —CR₁₁R₁₂R₃, or —NR₁₁R₁₂; wherein R₁₁ and R₁₂ aretaken together with the atom to which they are attached to form anoptionally substituted C₃-C₈ mono-cycloalkyl or an optionallysubstituted 3- to 8-membered mono-heterocyclic, wherein said cycloalkylor heterocyclic contains 0 to 3 substituents independently selected from═CR₁₃R₁₄, ═O, and ═NR₁₃; R₁₃ and R₁₄ are each independently selectedfrom the group consisting of hydrogen, halo, optionally substituted—C₁-C₈ alkyl, optionally substituted —C₂-C₈ alkenyl, optionallysubstituted —C₂-C₈ alkynyl, optionally substituted —C₃-C₈ cycloalkyl,optionally substituted 3- to 8-membered heterocyclic, optionallysubstituted aryl and optionally substituted heteroaryl; alternatively,R₁₃ and R₁₄ are taken together with the carbon atom to which they areattached to form an optionally substituted C₃-C₈ cycloalkyl; R₃ is aspreviously defined.

In yet another embodiment, the compound of Formula (I) is represented byFormula (IIa-2) or (IIb-2), or a pharmaceutically acceptable saltthereof, wherein M is —CR_(11′)R_(12′)R₃, or —NR_(11′)R_(12′); whereinR_(11′) and R_(12′) are taken together with the atom they are attachedto form an optionally substituted C₅-C₁₂ bi- or tri-cycloalkyl or anoptionally substituted 5- to 12-membered bi- or tri-heterocyclic,wherein said optionally substituted C₅-C₁₂ bi- or tri-cycloalkyl or anoptionally substituted 5- to 12-membered bi- or tri-heterocycliccomprises a first ring which includes the carbon atom to which R_(11′),R_(12′) and R₃ are attached or the nitrogen atom to which R_(11′) andR_(12′) are attached, a second ring and an optional third ring, whereinthe second ring is (1) spiro attached to the first ring, (2) fused tothe first ring or (3) formed by a 1,3- or 1,4-bridging group between tworing atoms of the first ring. Preferably, the first ring is a 3-, 4-,5-, 6- or 7-membered ring. R₃ is as previously defined.

In yet another embodiment, the compound of Formula (I) is represented byFormula (IIa-2) or (IIb-2), or a pharmaceutically acceptable saltthereof, wherein R is selected from the group consisting of—(CH₂)_(n)OR₁₁, —(CH₂)_(n)OC(O)R₁₁, —(CH₂)_(n)C(O)OR₁₁,—(CH₂)_(n)C(O)—NR₁₁R₁₂, —(CH₂)_(n)OC(O)OR₁₁, —(CH₂)_(n)O—C(O)NR₁₁R₁₂,—(CH₂)_(n)NR₁₁R₁₂, —(CH₂)_(n)NR₁₁C(O)R₁₁, —(CH₂)_(n)NR₁₁C(O)OR₁₁,—(CH₂)_(n)NR₁₁C(O)NR₁₁R₁₂, —(CH₂)_(n)S(O)R₁₂, —(CH₂)_(n)OS(O)₂R₁₂,—(CH₂)_(n)S(O)₂OR₁₁, —(CH₂)_(n)NR₁₁S(O)₂R₁₂, —(CH₂)_(n)S(O)₂NR₁₁R₁₂;—(CH₂)_(n)NR₁₁S(O)₂NR₁₁R₁₂; —(CH₂)_(n)OP(O)(OR₁₁)₂,—(CH₂)_(n)P(O)(OR₁₁)₂, —(CH₂)_(n)NR₁₁P(O)(OR₁₂)₂, and—(CH₂)_(n)P(O)—(NR₁₁R₁₂)₂; n, R₁₁ and R₁₂ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIa-3) or (IIb-3), or a pharmaceutically acceptable saltthereof:

wherein E at each occurrence is the same or different and independentlyselected from —CR₁₅R₁₆—, —C(O)—, —O—, —NR₁₆—, —S—, and —S(O)₂—; u is 0,1, 2, or 3; R₁₅ is hydrogen, halo, CN, —NR₁₁R₁₂, optionally substituted—C₁-C₈ alkyl, optionally substituted —C₂-C₈ alkenyl, optionallysubstituted —C₂-C₈ alkynyl, optionally substituted —C₃-C₈ cycloalkyl,optionally substituted 3- to 8-membered heterocyclic, optionallysubstituted aryl and optionally substituted heteroaryl; R₁₆ is hydrogen,optionally substituted —C₁-C₈ alkyl, optionally substituted —C₂-C₈alkenyl, optionally substituted —C₂-C₈ alkynyl, optionally substituted—C₃-C₈ cycloalkyl, optionally substituted 3- to 8-membered heterocyclic,optionally substituted aryl and optionally substituted heteroaryl;alternatively, R₁₅ and R₁₆ are taken together with the carbon atom towhich they are attached to form an optionally substituted C₃-C₇cycloalkyl or an optionally substituted 3- to 7-membered heterocyclic; vis 0, 1, 2, 3, or 4; X₁, A₁, A₂, R, Y, Z, R₁₁, and R₁₂ are as previouslydefined.

In certain embodiments, the present invention relates to compounds ofFormula (IIa-3) or (IIb-3) and pharmaceutically acceptable saltsthereof, wherein two vicinal E groups are taken together to form anoptionally substituted C═C double-bond or an optionally substitutedfused ring. In certain embodiments, two non-adjacent E groups are takentogether to form a bridging group.

In another embodiment, the compound of Formula (I) is represented byFormula (IIIa) or (IIIb), or a pharmaceutically acceptable salt thereof,

wherein u, B, X, A₁, A₂, Y, and E, are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (IIIa) or (IIIb) and pharmaceutically acceptable salts thereof,wherein two vicinal E groups are taken together to form a C═Cdouble-bond, a C═N double-bond or a fused ring. In certain embodiments,two remote E groups are taken together to form a bridging group.

In certain embodiments, the present invention relates to compounds ofFormula (IIIa) or (IIIb) or pharmaceutically acceptable salts thereof,wherein

is selected from the groups set forth below:

is selected from the groups set forth below:

wherein each of the above shown groups is optionally substituted; thepreferred substituents include halo, —OR₁₁, —NR₁₁R₁₂, —CN, —CO₂R₁₁,—C(O)NR₁₁R₁₂, optionally substituted methyl, and optionally substitutedphenyl; and R₁₁, R₁₂, R₃, R₅, and m′ are as previously defined.Alternatively, R₅ and R₁₁ are taken together with the nitrogen atom towhich they are attached to form an optionally substituted 3- to8-membered heterocyclic. More preferably, R₅ is selected from the groupsset forth below:

wherein each of the above shown groups is optionally substituted whenpossible; the preferred substituents include halo, —OR₁₁, —NR₁₁R₁₂, —CN,—CO₂R₁₁, —C(O)NR₁₁R₁₂, optionally substituted methyl, and optionallysubstituted phenyl. In another embodiment, R₅ is —SO₂NH₂.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIIa-1) or (IIIb-1), or a pharmaceutically acceptable saltthereof,

wherein A₁, A₂, X₁, m, B, Y, E, and u are as previously defined.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIIa-2) or (IIIb-2), or a pharmaceutically acceptable saltthereof,

wherein A₁, A₂, X₁, m, Y, E, and u are as previously defined.

In certain embodiment, the compound of Formula (I) is represented byFormula (IIIa-3) or (IIIb-3), or a pharmaceutically acceptable saltthereof,

wherein A₁, A₂, X₁, m, Y, E, and u are as previously defined.

In certain embodiment, the compound of Formula (I) is represented byFormula (IIIa-4) or (IIIb-4), or a pharmaceutically acceptable saltthereof,

wherein A₁, A₂, X₁, m, Y, R₅ and R₁₁ are as previously defined.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIIa-4) or (IIIb-4), or a pharmaceutically acceptable saltthereof, wherein A₁, A₂, X₁, m, R₅ and R₁₁ are as previously defined,and Y is optionally substituted azolyl. Preferably Y is optionallysubstituted pyrazolyl or oxazolyl.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIIa-5) or (IIIb-5), or a pharmaceutically acceptable saltthereof,

wherein A₁, A₂, X₁, m, Y, R₅ and R₁₁ are as previously defined.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIIa-5) or (IIIb-5), or a pharmaceutically acceptable saltthereof, wherein A₁, A₂, X₁, m, R₅ and R₁₁ are as previously defined,and Y is optionally substituted azolyl. Preferably Y is optionallysubstituted pyrazolyl or oxazolyl.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIIa-6) or (IIIb-6), or a pharmaceutically acceptable saltthereof,

wherein A₁, A₂, X₁, m, Y, R₅ and R₁₁ are as previously defined.

In certain embodiments, the compound of Formula (I) is represented byFormula (IIIa-6) or (IIIb-6), or a pharmaceutically acceptable saltthereof, wherein A₁, A₂, X₁, m, R₅ and R₁₁ are as previously defined,and Y is optionally substituted azolyl. Preferably Y is optionallysubstituted pyrazolyl or oxazolyl.

In another embodiment, the compound of Formula (I) is represented byFormula (IV), or a pharmaceutically acceptable salt thereof,

wherein, B, X, Y, Z, E and u are as previously defined.

In yet another embodiment, the compound of Formula (I) is represented byFormula (IVa) (IVb), (IVc), or a pharmaceutically acceptable saltthereof,

wherein each T is independently —CR₁₅, or N; X₁, m, Y, Z, E, u, and R₁₅are as previously defined. Preferably R₁₅ is H, halo, methyl or CF₃.

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principles ofchemical bonding. In some instances, it may be necessary to remove ahydrogen atom in order to accommodate a substituent at any givenlocation.

It will be yet appreciated that the compounds of the present inventionmay contain one or more asymmetric carbon atoms and may exist inracemic, diastereoisomeric, and optically active forms. It will still beappreciated that certain compounds of the present invention may exist indifferent tautomeric forms. All tautomers are contemplated to be withinthe scope of the present invention.

In one aspect, the compounds of the invention are useful in HBVtreatment by disrupting, accelerating, reducing, delaying and/orinhibiting normal viral capsid assembly and/or disassembly of immatureor mature particles, thereby inducing aberrant capsid morphology andleading to antiviral effects such as disruption of virion assemblyand/or disassembly, virion maturation, and/or virus egress. In oneembodiment, a disrupter of capsid assembly interacts with mature orimmature viral capsid to perturb the stability of the capsid, thusaffecting assembly and/or disassembly. In another embodiment, adisrupter of capsid assembly perturbs protein folding and/or saltbridges required for stability, function and/or normal morphology of theviral capsid, thereby disrupting and/or accelerating capsid assemblyand/or disassembly. In yet another embodiment, the compounds of theinvention bind capsid and alter metabolism of cellular polyproteins andprecursors, leading to abnormal accumulation of protein monomers and/oroligomers and/or abnormal particles, which causes cellular toxicity anddeath of infected cells. In another embodiment, the compounds of theinvention cause failure of the formation of capsid of optimal stability,affecting efficient uncoating and/or disassembly of viruses (e.g.,during infectivity).

In one embodiment, the compounds of the invention disrupt and/oraccelerate capsid assembly and/or disassembly when the capsid protein isimmature. In another embodiment, the compounds of the invention disruptand/or accelerate capsid assembly and/or disassembly when the capsidprotein is mature. In yet another embodiment, the compounds of theinvention disrupt and/or accelerate capsid assembly and/or disassemblyduring vial infectivity. In yet another embodiment, the disruptionand/or acceleration of capsid assembly and/or disassembly attenuates HBVviral infectivity and/or reduces viral load. In yet another embodiment,disruption, acceleration, inhibition, delay and/or reduction of capsidassembly and/or disassembly eradicates the virus from the host organism.In yet another embodiment, eradication of the HBV from a hostadvantageously obviates the need for chronic long-term therapy and/orreduces the duration of long-term therapy.

In one embodiment, the compounds described herein are suitable formonotherapy and are effective against natural or native HBV strains andagainst HBV strains resistant to currently known drugs. In anotherembodiment, the compounds described herein are suitable for use incombination therapy.

In another embodiment, the compounds of the invention can be used inmethods of modulating (e.g., inhibit, disrupt or accelerate) theactivity of HBV cccDNA. In yet another embodiment, the compounds of theinvention can be used in methods of diminishing or preventing theformation of HBV cccDNA. In another embodiment, the additionaltherapeutic agent is selected from immune modulator or immune stimulatortherapies, which includes T-cell response activator AIC649 andbiological agents belonging to the interferon class, such as interferonalpha 2a or 2b or modified interferons such as pegylated interferon,alpha 2a, alpha 2b, lamda; or TLR modulators such as TLR-7 agonists orTLR-9 agonists; or therapeutic vaccines to stimulate an HBV-specificimmune response such as virus-like particles composed of HBcAg andHBsAg, immune complexes of HBsAg and HBsAb, or recombinant proteinscomprising HBx, HBsAg and HBcAg in the context of a yeast vector; orimmunity activator such as SB-9200 of certain cellular viral RNA sensorssuch as RIG-I, NOD2, and MDA5 protein, or RNA interence (RNAi) or smallinterfering RNA (siRNA) such as ARC-520, ARC-521, ARB-1467, and ALN-HBVRNAi, or antiviral agents that block viral entry or maturation or targetthe HBV polymerase such as nucleoside or nucleotide or non-nucleos(t)idepolymerase inhibitors, and agents of distinct or unknown mechanismincluding agents that disrupt the function of other essential viralprotein(s) or host proteins required for HBV replication or persistencesuch as REP 2139. In an embodiment of the combination therapy, thereverse transcriptase inhibitor is at least one of Zidovudine,Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Aba-cavir,Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin,acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir,Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine,Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the TLR-7 agonist isselected from the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad-enine), AZD 8848 (methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl] amino Imethyl)phenyl] acetate), GS-9620(4-Amino-2-butoxy-8-[3-(1-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone),and RO6864018.

In an embodiment of these combination therapies, the compound and theadditional therapeutic agent are co-formulated. In another embodiment,the compound and the additional therapeutic agent are co-administered.

In another embodiment of the combination therapy, administering thecompound of the invention allows for administering of the additionaltherapeutic agent at a lower dose or frequency as compared to theadministering of the at least one additional therapeutic agent alonethat is required to achieve similar results in prophylactically treatingan HBV infection in an individual in need thereof.

In another embodiment of the combination therapy, before administeringthe therapeutically effective amount of the compound of the invention,the individual is known to be refractory to a compound selected from thegroup consisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In still another embodiment of the method, administering the compound ofthe invention reduces viral load in the individual to a greater extentcompared to the administering of a compound selected from the groupconsisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In another embodiment, administering of the compound of the inventioncauses a lower incidence of viral mutation and/or viral resistance thanthe administering of a compound selected from the group consisting of aHBV polymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and combination thereof.

It should be understood that the compounds encompassed by the presentinvention are those that are suitably stable for use as pharmaceuticalagent.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system thatcomprises at least one aromatic ring. Polycyclic aryls can comprisefused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fusedrings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ringsystem consisting of two rings wherein at least one ring is aromatic;and the two rings can be fused or covalently attached.

The term “azole group,” as used herein, refers to 5-memberedheteroaromatic ring containing at least one nitrogen atom. Preferredazole groups contain a nitrogen atom and at least one additionalheteroatom, preferably a nitrogen, oxygen or sulfur atom. Azole groupsinclude, but are not limited to pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl. Anazole group is termed “ortho” substituted in reference to twosubstituents which are on adjacent ring atoms. An azole group is termed“meta” substituted in reference to two substituents which are not onadjacent ring positions.

The term “bicyclic azole” or “bicyclic azole group” refers to anaromatic ring system consisting of two rings wherein at least one ringis azole group; and the two rings can be fused or covalently attached.Preferred bicyclic azole groups are those in which an azole ring isfused to a six-membered aromatic or heteroaromatic ring. Such groupsinclude, but are not limited to, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,imidazolopyridyl, pyrazolopyridyl, thiazolopyridyl, oxazolopyridyl,isoxazolopyridyl, triazolopyridyl, and tetrazolopyridyl.

The term “alkyl” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals. “C₁-C₄ alkyl,” “C₁-C₆ alkyl,”“C₁-C₈ alkyl,” “C₁-C₁₂ alkyl,” “C₂-C₄ alkyl,” or “C₃-C₆ alkyl,” refer toalkyl groups containing from one to four, one to six, one to eight, oneto twelve, 2 to 4 and 3 to 6 carbon atoms respectively. Examples ofC₁-C₈ alkyl radicals include, but are not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl andoctyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. “C₂-C₈ alkenyl,” “C₂-C₁₂alkenyl,” “C₂-C₄ alkenyl,” “C₃-C₄ alkenyl,” or “C₃-C₆ alkenyl,” refer toalkenyl groups containing from two to eight, two to twelve, two to four,three to four or three to six carbon atoms respectively. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. “C₂-C₈ alkynyl,” “C₂-C₁₂alkynyl,” “C₂-C₄ alkynyl,” “C₃-C₄ alkynyl,” or “C₃-C₆ alkynyl,” refer toalkynyl groups containing from two to eight, two to twelve, two to four,three to four or three to six carbon atoms respectively. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic orpolycyclic saturated carbocyclic ring or a bi- or tri-cyclic groupfused, bridged or spiro system, and the carbon atoms may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic doublebond. Preferred cycloalkyl groups include C₃-C₁₂ cycloalkyl, C₃-C₆cycloalkyl, C₃-C₈ cycloalkyl and C₄-C₇ cycloalkyl. Examples of C₃-C₁₂cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl,4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl,spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, andthe like.

The term “cycloalkenyl”, as used herein, refers to monocyclic orpolycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridgedor spiro system having at least one carbon-carbon double bond and thecarbon atoms may be optionally oxo-substituted or optionally substitutedwith exocyclic olefinic double bond. Preferred cycloalkenyl groupsinclude C₃-C₁₂ cycloalkenyl, C₃-C₈ cycloalkenyl or C₅-C₇ cycloalkenylgroups. Examples of C₃-C₁₂ cycloalkenyl include, but not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl,spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl,and the like.

As used herein, the term “arylalkyl” means a functional group wherein analkylene chain is attached to an aryl group, e.g., —CH₂CH₂-phenyl. Theterm “substituted arylalkyl” means an arylalkyl functional group inwhich the aryl group is substituted. Similarly, the term“heteroarylalkyl” means a functional group wherein an alkylene chain isattached to a heteroaryl group. The term “substituted heteroarylalkyl”means a heteroarylalkyl functional group in which the heteroaryl groupis substituted.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms connected to the rest of the moleculevia an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy,2-propoxy (isopropoxy) and the higher homologs and isomers. Preferredalkoxy are (C₁-C₃) alkoxy.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH,NH, NH₂, C(O), S(O)₂, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH,S(O)₂NH₂, NHC(O)NH₂, NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂,C(O)NHS(O)₂NH or C(O)NHS(O)₂NH₂, and the like, groups comprising one ormore functional groups, non-aromatic hydrocarbons (optionallysubstituted), and groups wherein one or more carbons of a non-aromatichydrocarbon (optionally substituted) is replaced by a functional group.Carbon atoms of an aliphatic group can be optionally oxo-substituted. Analiphatic group may be straight chained, branched, cyclic, or acombination thereof and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, as used herein, aliphaticgroups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls,such as polyalkylene glycols, polyamines, and polyimines, for example.Aliphatic groups may be optionally substituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused, bridged or spiro system, where (i) each ringsystem contains at least one heteroatom independently selected fromoxygen, sulfur and nitrogen, (ii) each ring system can be saturated orunsaturated (iii) the nitrogen and sulfur heteroatoms may optionally beoxidized, (iv) the nitrogen heteroatom may optionally be quaternized,(v) any of the above rings may be fused to an aromatic ring, and (vi)the remaining ring atoms are carbon atoms which may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic doublebond. Representative heterocycloalkyl groups include, but are notlimited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl,quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl,8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl,1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl.Such heterocyclic groups may be further substituted. Heteroaryl orheterocyclic groups can be C-attached or N-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphaticmoiety or the like, described herein can also be a divalent ormultivalent group when used as a linkage to connect two or more groupsor substituents, which can be at the same or different atom(s). One ofskill in the art can readily determine the valence of any such groupfrom the context in which it occurs.

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms with substituentsincluding, but not limited to, —F, —C₁, —Br, —I, —OH, C₁-C₁₂-alkyl;C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, —C₃-C₁₂-cycloalkyl, protected hydroxy,—NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₈-alkenyl, —NH—C₂-C₈-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH— heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O— heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl,—CONH—C₂-C₈-alkynyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl,—CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —CO₂—C₁-C₁₂ alkyl,—CO₂—C₂-C₈ alkenyl, —CO₂—C₂-C₈ alkynyl, CO₂—C₃-C₁₂-cycloalkyl,—CO₂-aryl, CO₂-heteroaryl, CO₂-heterocyloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocyclo-alkyl, —NHC(O)H, —NHC(O)—C₁-C₁₂-alkyl,—NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl,—NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclo-alkyl,—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl, —NHCO₂—C₂-C₈-alkynyl,—NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl,—NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl,—NHC(O)NH—C₂-C₈-alkenyl, —NHC(O)NH—C₂-C₈-alkynyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl,—NHC(S)NH—C₂-C₈-alkenyl, —NHC(S)NH—C₂-C₈-alkynyl,—NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl,—NHC(NH)NH—C₂-C₈-alkenyl, —NHC(NH)NH—C₂-C₈-alkynyl,—NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl,—NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH—C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,cycloalkyls and the like can be further substituted.

The term “halo” or halogen” alone or as part of another substituent, asused herein, refers to a fluorine, chlorine, bromine, or iodine atom.

The term “optionally substituted”, as used herein, means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

The term “hydroxy activating group,” as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

The term “protic solvent,” as used herein, refers to a solvent thattends to provide protons, such as an alcohol, for example, methanol,ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Suchsolvents are well known to those skilled in the art, and it will beobvious to those skilled in the art that individual solvents or mixturesthereof may be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable,” as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the Formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject,” as used herein, refers to an animal. Preferably, theanimal is a mammal. More preferably, the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt,” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentane-propionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intra-arterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectable.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to Van Devanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference).

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections, conditions are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the present invention described herein can, forexample, be administered by injection, intravenously, intra-arterial,subdermally, intraperitoneally, intramuscularly, or subcutaneously; ororally, buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the Formula described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes butnot limited to, immune therapies (eg. interferon), therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines(e.g. theophylline), mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists),anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial and anti-viral agents(e.g. ribavirin and amantidine). The compositions according to theinvention may also be used in combination with gene replacement therapy.

Combination and Alternation Therapy

It has been recognized that drug-resistant variants of HIV, HBV and HCVcan emerge after prolonged treatment with an antiviral agent. Drugresistance most typically occurs by mutation of a gene that encodes fora protein such as an enzyme used in viral replication, and mosttypically in the case of HIV, reverse transcriptase, protease, or DNApolymerase, and in the case of HBV, DNA polymerase, or in the case ofHCV, RNA polymerase, protease, or helicase. Recently, it has beendemonstrated that the efficacy of a drug against HIV infection can beprolonged, augmented, or restored by administering the compound incombination or alternation with a second, and perhaps third, antiviralcompound that induces a different mutation from that caused by theprinciple drug. The compounds can be used for combination are selectedfrom the group consisting of a HBV polymerase inhibitor, interferon, TLRmodulators such as TLR-7 agonists or TLR-9 agonists, therapeuticvaccines, immune activator of certain cellular viral RNA sensors, viralentry inhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof. Alternatively, the pharmacokinetics,biodistribution, or other parameter of the drug can be altered by suchcombination or alternation therapy. In general, combination therapy istypically preferred over alternation therapy because it induces multiplesimultaneous stresses on the virus.

Preferred compounds for combination or alternation therapy for thetreatment of HBV include 3TC, FTC, L-FMAU, interferon, adefovirdipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3′-valinylL-dC), β-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine(DAPD), and β-D-dioxolanyl-6-chloropurine (ACP), famciclovir,penciclovir, lobucavir, ganciclovir, and ribavirin.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBNfor azobisisobutyronitrile; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O fordi-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for1-methyl-1-(4-biphenylyl)ethyl carbonyl; Bz for benzoyl; Bn for benzyl;BocNHOH for tert-butyl N-hydroxycarbamate; t-BuOK for potassiumtert-butoxide; Bu₃SnH for tributyltin hydride; BOP for(benzotriazol-1-yloxy)tris(dimethylamino)phospho-niumHexafluorophosphate; Brine for sodium chloride solution in water; BSAfor N,O-bis(trimethylsilyl)acetamide; CDI for carbonyldiimidazole; DCMor CH₂C₁₂ for dichloro-methane; CH₃ for methyl; CH₃CN for acetonitrile;Cs₂CO₃ for cesium carbonate; CuCl for copper (I) chloride; CuI forcopper (I) iodide; dba for dibenzylidene acetone; dppb fordiphenylphos-phinobutane; DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene;DCC for N,N′-dicyclohexyl-carbodiimide; DEAD fordiethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or(i-Pr)₂EtN for N,N,-diisopropylethyl amine; Dess-Martin periodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP for4-dimethylamino-pyridine; DME for 1,2-dimethoxyethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT fordi(p-methoxyphenyl)-phenylmethyl or dimethoxy-trityl; DPPA fordiphenylphosphoryl azide; EDC forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; EDC HCl forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumHexafluoro-phosphate; HCl for hydrogen chloride; HOBT for1-hydroxybenzotriazole; K₂CO₃ for potassium carbonate; n-BuLi forn-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium;PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP forlithium 2,2,6,6-tetramethyl-piperidinate; MeOH for methanol; Mg formagnesium; MOM for methoxymethyl; Ms for mesyl or —SO₂—CH₃; Ms₂O formethanesulfonic anhydride or mesyl-anhydride; MTBE for t-butyl methylether; NaN(TMS)₂ for sodium bis(trimethylsilyl)amide; NaCl for sodiumchloride; NaH for sodium hydride; NaHCO₃ for sodium bicarbonate orsodium hydrogen carbonate; Na₂CO₃ sodium carbonate; NaOH for sodiumhydroxide; Na₂SO₄ for sodium sulfate; NaHSO₃ for sodium bisulfite orsodium hydrogen sulfite; Na₂S₂O₃ for sodium thiosulfate; NH₂NH₂ forhydrazine; NH₄HCO₃ for ammonium bicarbonate; NH₄Cl for ammoniumchloride; NMO for N-methylmorpholine N-oxide; NaIO₄ for sodiumperiodate; Ni for nickel; OH for hydroxyl; OsO₄ for osmium tetroxide;PPA for polyphophoric acid; PTSA forp-toluenesulfonic acid; PPTS forpyridiniump-toluenesulfonate; PhI(OPiv)₂ forBis(tert-butylcarbonyloxy)iodobenzene; Rh₂(Esp)₂ forBis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]; TBAFfor tetrabutylammonium fluoride; TEA or Et₃N for triethylamine; TES fortriethylsilyl; TESCI for triethylsilyl chloride; TESOTf fortriethylsilyl trifluoromethanesulfonate; TFA for trifluoroacetic acid;THF for tetrahydrofuran; TMEDA forN,N,N′,N′-tetramethylethylene-diamine; TPP or PPh₃ fortriphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Ts fortosyl or —SO₂—C₆H₄CH₃; Ts₂O for tolylsulfonic anhydride ortosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph forphenyl; POPd for dihydrogendichlorobis(di-tert-butylphosphinito-KP)palladate(II); Pd₂(dba)₃ fortris(diben-zylideneacetone) dipalladium (0); Pd(PPh₃)₄ fortetrakis(triphenylphosphine)-palladium (0); PdCl₂(PPh₃)₂ fortrans-dichlorobis-(triphenylphosphine)palladium (II); Pt for platinum;Rh for rhodium; rt for room temperature; Ru for ruthenium; TBS fortert-butyl dimethylsilyl; TMS for trimethylsilyl; or TMSCl fortrimethylsilyl chloride.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared. These schemes are of illustrative purpose, and are not meantto limit the scope of the invention. Equivalent, similar, or suitablesolvents, reagents or reaction conditions may be substituted for thoseparticular solvents, reagents, or reaction conditions described hereinwithout departing from the general scope of the method of synthesis.

The nature of the group B in Formula I will have a significant effect onthe choice of the synthesis methods, as demonstrated below.

When B in Formula I is a hydrogen, an illustrative method is shown inSchemes 1, the X, A, Y, Z are as defined as previously for formula I.The starting material aldehyde I-1, a ketone I-2 wherein Y is anelectron withdrawing group, such as an ester, or an aromatic group (thedesired aryl or heteroaryl) and an amidine I-3 are all eithercommercially available or can be easily prepared by those familiar withthe skill of the arts. The dihydropyrimidine core I-4 can be prepared inone pot process from an aldehyde I-1, a ketone I-2 and an amidine I-3(or its salt) in the presence of a suitable base as such potassiumacetate or potassium bicarbonate in a solvent like methanol, ortrifluoroethanol. Most frequently, elevated temperature is required forthis transformation. Starting from this core 1-4, A, X, Y, Z could beindividually manipulated and converted to varieties of functionalgroups.

For instance, when Z in I-4 is a methyl, this methyl can be furtherfunctionalized easily. One specific example is shown in scheme 1a, whenI-4a is treated with NBS, the methyl bromide I-5 will be obtained. Thebromide can be displaced with nucleophiles. Therefore, when I-5a isreacted with various bi-functional molecules Z′(CH₂)_(m)GH, in which GHis a nucleophile, such as an amine, an alcohol or a malonate; Z′ isprecursor of a leaving group, such as a protected hydroxyl or a ester,in the presence of a suitable base such as TEA or pyridine, will providea more complicated structure I-6a. Next the Z′ is converted to a desiredleaving group by either de-protection or reduction to free the alcohol,followed by mesylate formation to afford the 1-7a. Alternatively,bromide or tosylate may be used. When 1-7a is treated with a base, likeTEA or K₂CO₃, in a proper solvent such as THF, acetonitrile or DMF willgive the cyclized product 1-8a.

Next, Y in the formula I-8a can be further manipulated. For instance, asshown in Scheme 1b, wherein Y is an ester, R₃ is as defined aspreviously. In the case while R₃ is t-Butyl or allyl, then ester I-8bcan be converted to an advanced carboxyl acid intermediate I-9b whentreated with strong acid (HCl or TFA) or Pd(PPh₃)₄/Morpholine,respectively. By taking advantage of this carboxyl acid as a keyintermediate, various functional groups can be generated from it. Onespecific example is shown in the same scheme, this carboxyl acid isconverted to the acyl chloride followed by treating with amines to givethe amide I-10b. Alternatively this transformation also can be completedin the presence of a dehydration reagent such as EDC or DCC as well as abase like TEA, DIPEA. When R₁ and R₂ are hydrogen, this amide whentreated with a dehydration reagent such as TFAA will afford a nitrile.This nitrile can serve as advanced intermediate for azoles. When R₁ ismethyl, R₂ is methoxyl, a Weinreb amide is obtained. In the next step,this Weinreb amide is reduced to an aldehyde or reacted with all sortsof Grignard reagent will offer various ketone, which could serve aslater stage intermediate for further functional group manipulation formore complicated heteroaryl including azoles. One example is shown inthe same scheme, the Weinreb amide I-10b can be reduced to afford thealdehyde I-11b, which when reacted with acetone in the presence of abase such as LDA will offer the α,β-unsaturated ketone 1-12b. I-12b istreated with hydroxyl amine followed by an iodine induced cyclization toafford the isoxazole I-13c. More related arts can be found in thevarious publications (for example, J. A Joule and K. Mills, HeterocyclicChemistry, 5^(th) edition, 557 and reference therein). G, m′ and R₃ areas previously defined.

In yet another specific example as shown in Scheme 1c, when the carboxylacid I-9b is treated with pyridinium tribromide in the presence a basesuch as pyridine, a bromide I-10c will be produced. The bromide reactswith various aryl or heteroaryl boronic ester/acid or tin reagent, whichcan be commercial available or easily prepared by those familiar withthe skill of the arts, under the Pd(0) catalyzed coupling conditions togive the target molecule I-11c. (see reviews: A. Suzuki, Pure AppliedChem., 1991, 63, 419; A. Suzuki, Handbook of Organopalladium Chemistryfor Organic Synthesis, 2002, 1, 249; A. Anastasia, et al, Handbook ofOrganopalladium Chemistry for Organic Synthesis, 2002, 1, 311).

In yet another specific example as shown Scheme 1d, the compound I-4dcan be protected with a proper protecting group such as Boc, or Cbz togive I-5d. Hydrolysis the ester of I-5d following similar procedure asdescribed in Scheme 1b will afford the acid I-6d. When the carboxyl acidI-6d is treated with at least two equivalents of NBS, the di-bromocompound I-7d will be obtained. Starting from this di-bromo I-7d,following similar chemical procedure described in Scheme 1a forconverting I-5a to I-8a, the 5-bromo compound I-10c will be generated.From it, target I-11c will be obtained as discussed in Scheme 1c.

In yet another specific example as shown Scheme 1e, if the amidine I-3shown in Scheme 1 is replaced with a urea, a dihydropyrimidine-2-oneI-4a analogue to I-4 is generated. It is well known in literature (A.Karnail, et al, Journal of Organic Chemistry, 1989, 54, 5898) that whenthis family molecules are treated with (Boc)₂O in the present of a basesuch as TEA, or DIPEA, a N-3 Boc protected product I-5e will beobtained. Alkylation of this intermediate I-5e with an alkylationreagent, like RBr with the desired R group in the presence of a properbase such as NaH will afford the N-1 alkylated intermediate I-6e. WhenI-6e is treated with an acid, like HCl or TFA, the N-3 Boc protectinggroup will be removed, which is followed by heating this material inPOCl₃ to lead to the 2-chloro dhydropyrimidine I-7e. This chloridereacts with various aryl or heteroaryl boronic ester/acid or tinreagent, which can be commercial available or easily prepared by thosefamiliar with the skill of the arts, under the Pd(0) catalyzed couplingconditions to give the target molecule I-8e contains the desired Agroup. When I-8e is reacted with 1 equivalent NBS, the 6-methyl will bebrominated to offer advanced intermediated I-9e. The bromide in I-9e canbe displaced with the desired M group with MH in the presence of properbase to afford I-10e. In molecule I-10e, if the Y is desired aryl orheteroaryl group, then I-10e is a desired target; if Y is an ester, thenall the chemistry described in Scheme 1b and Scheme 1c can be applied toafford the desired product. R and M are as previously defined.

On the other hand, if the R in I-9e contains a nucleophile such as I-9e′as shown in Scheme 1f, when treated with a base, TEA, or NaH will affordthe intermediate I-8a.

On the other hand when B is CN or an alkyl group, a step wise route isrequired for the preparation of the final targets. As illustrated inScheme 2, aldehyde I-1 and I-2 are reacted with each other in thepresence of a catalyst system, such as piperidine/acetic acid to affordthe α,β-unsaturated ketone II-1. This α,β-unsaturated ketone II-1 reactswith a copper reagent CuB, which can be commercially available or can beeasily generated in situ from CuI and BMgX (or BLi). The newly formedα,β-unsaturated ketone II-2 then reacts with I-3 in a similar processdescribed above as in the one-pot process to afford the desired targetI.

In a specific example, while B is a methyl, X is a aryl or heteroaryl, Iin Scheme 2 can be introduced with a chemistry described in Scheme 2afollowing similar published precedents (For example, WO 2013/102655). Adistal acetylene I-1a served as a methyl ketone equivalent reacts withketone I-2 in the presence of InCl₃ will provide the α,β-unsaturatedketone II-1a, which in turn when reacts with amidine I-3 will provideIa, the 4-methyl analogue of I.

With I in hand, all the chemistry described in Scheme 1a to Scheme 1fcan be applied here to give the desired targets.

Alternatively, in certain cases, even when B is hydrogen, a step wiseprocedure similar as in Scheme 2 is required to achieve the targets.

It will be appreciated that, with appropriate manipulation andprotection of any chemical functionality, synthesis of compounds ofFormula (I) is accomplished by methods analogous to those above and tothose described in the Experimental section. Suitable protecting groupscan be found, but are not restricted to, those found in T W Greene and PG M Wuts “Protective Groups in Organic Synthesis”, 3rd Ed (1999), JWiley and Sons.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.

Step 1-1a. A solution of ethyl (R)-2-hydroxypropanoate (5 g, 42.3 mmol)and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (6 g, 42.3 mmol) was stirred for4 hours at 120° C. The mixture was concentrated under vacuum to givedesired product (9 g, crude) as yellow oil, which was used in the nextstep without further purification. ESI MS m/z=203.25 [M+H]⁺.

Step 1-1b. A solution of the compound from step 1-1a (5 g, 24.5 mmol),2-chloro-4-fluorobenzaldehyde (4.3 g, 27.3 mmol), TsOH (cat) and HOAc(cat) in toluene (60 mL) was stirred at 110° C. overnight. The mixturewas concentrated. The residue was chromatographed (silica, ethylacetate/petroleum ether) to give the desired product (5.93 g, 70.0%) asyellow solid. ESI MS m/z=343.00 [M+H]⁺.

Step 1-1c. A solution of the compound from step 1-1b (5 g, 14.6 mmol),thiazole-2-carboximidamide HCl salt (2.38 g, 14.6 mmol) and K₂CO₃ (2.01g, 14.6 mmol) in DMF (20 mL) was stirred for 2 hours at 80° C. It wasdiluted with EtOAc and washed with brine, filtered and concentrated.After the residue was purified by silica gel column (ethylacetate/petroleum ether), the mixture was recrystallized from EtOH at 0°C. to give the desired product as yellow solid (1.25 g, 25.0%). ESI MSm/z=452.05 [M+H]⁺.

Step 1-1d. A solution of the compound from step 1-1c (950 mg, 2.10mmol), (Boc)₂O (915.6 mg, 4.20 mmol) and DMAP (307 mg, 2.51 mmol) in DCM(30 mL) was stirred for 1 hour at rt. The reaction mixture wasconcentrated. The residue was chromatographed (silica, ethylacetate/petroleum ether) to give the desired compound as yellow solid(1.07 g, 92%). ESI MS m/z=552.30 [M+H]⁺.

Step 1-1e. A solution of the compound from step 1-1d (965 mg, 1.75 mmol)in a solution of NaOH [40 mL, 2M in H₂O/MeOH (1:5)] was stirred for 18hours at rt. After being acidified with aq HCl (4N) to pH 5, the mixturewas extracted with DCM. The organic layer was washed with aq. NH₄Cl andH₂O, dried (Na₂SO₄) and concentrated. The residue was chromatographed(silica, ethyl acetate/petroleum ether) to give the desired compound asyellow solid (620 mg, 78%). ESI MS m/z=452.15 [M+H]⁺.

Step 1-1f. A solution of the compound from step 1-1e (250 mg, 0.55 mmol)in DCM (10 mL) was treated with NBS (295 mg, 1.66 mmol) for 6 hours atrt. The reaction was quenched by the addition of water (2 mL) andextracted with DCM. The organic layer was dried (Na₂SO₄), concentrated.The residue was chromatographed (Cis column, MeCN/H₂O) to give the titlecompound as yellow solid (103.5 mg, 33%). ESI MS m/z=566.10, 568.10[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (m, 2H), 7.98 (d, 1H), 7.57 (m,1H), 7.23 (m, 1H), 6.35 (s, 1H), 4.45 (m, 2H), 1.15 (s, 9H).

Step 2-2a. To a solution of 1-ethynyl-4-fluorobenzene (21.500 g, 179mmol) and allyl acetoacetate (25.4 g, 179 mmol) in xylene (170 ml) at rtwas added indium (III) trifluoromethanesulfonate (2.012 g, 3.58 mmol).The mixture was heated at 120° C. for 3 h before being allowed to cooldown and concentrated. The residue was diluted with DCM and hexanes(˜2/1) and filtered. The filtrate was directly purified by flash columnchromatography (silica, hexanes/EtOAc) to afford the desired compound asyellow oil (25.80 g, 55%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.23-7.16 (m,2H), 7.09-7.00 (m, 2H), 5.98-5.89 (m, 0.5H), 5.66-5.56 (m, 0.5H),5.37-5.24 (m, 1H), 5.18-5.08 (m, 1H), 4.70 (dt, J=5.7, 1.4 Hz, 1H), 4.41(dt, J=6.0, 1.3 Hz, 1H), 2.40 (s, 1.5H), 2.35 (s, 1.5H), 2.30 (s, 1.5H),1.90 (s, 1.5H).

Step 2-2b. To a mixture of thiazole-2-carboximidamide hydrochloride(5.49 g, 33.6 mmol) and sodium bicarbonate (5.64 g, 67.1 mmol) in NMP(46 ml) at 120° C. was added a solution of the compound from Step 2-2a(8.80 g, 33.6 mmol) in NMP (20 ml). The mixture was heated at 120° C.under N₂ for 2.5 h before being allowed to cool down and diluted withMTBE and water. The organic layer was washed with water (*1), brine(*1), dried over Na₂SO₄ (s), filtered and concentrated. The residue waspurified by flash column chromatography (silica, hexanes/EtOAc) toafford the desired compound as yellow oil (5.10 g, 41%). ESI MSm/z=372.13 [M+H]⁺.

Step 2-2c. A solution of the compound from step 2-2b (5.10 g, 13.73mmol), (Boc)₂O (5.74 ml, 24.72 mmol) and DMAP (3.35 g, 27.5 mmol) in DCM(60 ml) was stirred at rt for 3 h. The mixture was directly purified byflash column chromatography (silica, hexanes/EtOAc) to afford thedesired compound as orange oil (5.50 g, 85%). ESI MS m/z=472.18 [M+H]⁺.

Step 2-2d. To a mixture of the compound from step 2-2c (0.630 g, 1.336mmol) and morpholine (0.122 ml, 1.403 mmol) in THF (8 ml) at rt wasadded Pd(PPh₃)₄ (0.077 g, 0.067 mmol). The mixture was stirred at rtunder N₂ for 1.5 h before being concentrated. The residue was taken upwith EtOAc and water. 1 N HCl aq (˜1.5 ml) was added to get 2 clearlayers. The organic layer was washed with brine (*1), dried over Na₂SO₄(s), filtered and concentrated. The residue was purified by flash columnchromatography (silica, hexanes/EtOAc) to afford the desired compound asyellow foam (0.576 g, 100%). ESI MS m/z=432.14 [M+H]⁺.

Step 2-2e. To a solution of the compound from step 2-2d (0.290 g, 0.672mmol) in DCM (6 ml) and heptane (6.00 ml) at rt was added NBS (0.251 g,1.411 mmol). The resulting suspension was stirred at rt for 20 h beforebeing diluted with DCM and saturated NaHCO₃ aq. The aqueous layer wasextracted with DCM (*1). The combined organic layers were dried overNa₂SO₄ (s), filtered and concentrated. The residue was purified by flashcolumn chromatography (silica, hexanes/EtOAc) to afford the titlecompound as colorless foam (0.344 g, 94%). ESI MS m/z=543.97, 545.97,547.97 [M+H]⁺.

Example 1

Step 1a. To a solution of ethyl 2-nitroacetate (0.941 g, 7.07 mmol) inDMF (50 ml) at rt was added NaH (60% in mineral oil, 0.283 g, 7.07mmol). The resulting solution was stirred at rt for 1 h before beingcooled down to 0° C. Intermediate 1 (2.000 g, 3.54 mmol) was added at 0°C. The resulting solution was stirred at 0° C. for 2 h and then at rtovernight. It was quenched with saturated NH₄Cl aq and diluted with DCMand EtOAc. The organic layer was washed with water (*1), brine (*2),dried (Na₂SO₄) and concentrated. The residue was chromatographed(silica, hexanes/EtOAc) to afford the desired compound as yellow foam(0.903 g, 41%). ESI MS m/z=617.03, 619.03 [M+H]⁺.

Step 1b. To a solution of the compound from step 1a (450 mg, 0.728 mmol)and 1-methyl-3-(tributylstannyl)-1H-pyrazole (351 mg, 0.947 mmol) intoluene (12 ml) at rt was added Pd(Ph₃P)₄ (126 mg, 0.109 mmol). Themixture was degassed 3 times before being heated at 135° C. using amicrowave reactor for 45 min. The above reaction was repeated once. Thereaction mixtures were combined and directly chromatographed (silica,hexanes/EtOAc) to afford the desired compound as yellow foam (525.0 mg,58%). ESI MS m/z=619.16, 621.15 [M+H]⁺.

Step 1c. A clear yellow-orange solution of the compound from step 1b (60mg, 0.097 mmol) in DCM (2.0 ml) and TFA (1.0 ml) was stirred at rt for 1h before being concentrated. The residue was co-evaporated with toluene(*2), then with DCM and some DIPEA. The residue was chromatographed(silica, hexanes/EtOAc) to afford the desired compound as yellow foam(42.0 mg, 84%). ESI MS m/z=519.10, 521.11 [M+H]⁺.

Step 1d. Raney 2800 Ni (excess, slurry in Water) was washed with THF(*3). A solution of the compound from step 1c (42 mg, 0.081 mmol) in THF(2 ml) was added at rt, followed by (Boc)₂O (0.056 ml, 0.243 mmol). Theresulting mixture was stirred at 50° C. with a H₂ balloon for 6 h. Itwas diluted with MeOH and filtered through a short pad of celite,washing with DCM/MeOH (1/1). The filtrate was concentrated. The residuewas chromatographed (silica, hexanes/EtOAc) to afford the desiredcompound as yellow foam (21.0 mg, 44%). ESI MS m/z=589.18, 591.18[M+H]⁺.

Step 1e. To a solution of the compound from step 1d (21 mg, 0.036 mmol)in THF (2 ml) was added LiBH₄ (excess). The mixture was heated at 75° C.for 45 min before being allowed to cool down. 0.5 N HCl solution wasadded dropwise until no bubble was observed. The mixture was dilutedwith EtOAc and water. The organic layer was washed with brine, dried(Na₂SO₄) and concentrated. The residue was chromatographed (silica,hexanes/EtOAc) to afford the desired compound as yellow foam (11.8 mg,60%). ESI MS m/z=547.17, 549.17 [M+H]⁺.

Step 1f. To a solution of the compound from step 1e (11.8 mg, 0.022mmol) in DCM (2 ml) at 0° C. was added Et₃N (6.01 μl, 0.043 mmol),followed by MsCl (2.52 μl, 0.032 mmol). The resulting mixture wasstirred at 0° C. for 1 h before being diluted with DCM and water. Theaqueous layer was extracted with DCM (*2). The combined organic layerswere dried (Na₂SO₄) and concentrated. The residue was dried under vacuumto afford the desired compound as yellow foam (13.5 mg, 100%). ESI MSm/z=625.15, 627.15 [M+H]⁺. MS showed ˜50% of the product alreadycyclized.

Step 1 g. To a solution of the compound from step 1f (13.5 mg, 0.022mmol) in DCM (2 ml) at rt was added Et₃N (6.02 μl, 0.043 mmol). Theresulting mixture was stirred at rt for 1.5 h and then at 40° C. for 4h. It was concentrated. The residue was chromatographed (silica,hexanes/EtOAc) to afford the title compound as yellow foam (10.0 mg,88%). ESI MS m/z=529.16, 531.16 [M+H]⁺.

Example 2

Step 2a. To a solution of Example 1 (10.0 mg, 0.019 mmol) in DCM (2 ml)at rt was added 4N HCl in 1,4-dioxane (0.095 ml, 0.378 mmol). Theresulting suspension was stirred at rt for 1 h. More 4 N HCl in1,4-dioxane (0.095 ml, 0.378 mmol) was added. The suspension was stirredat rt for 1 h before being concentrated. The residue was co-evaporatedwith toluene and dried under vacuum to afford the desired compound asyellow foam (8.5 mg, 100%). ESI MS m/z=429.11, 431.11 [M+H]⁺.

Step 2b. To a solution of the compound from step 2a (8.5 mg, 0.019 mmol)in pyridine (1 ml) at rt was added cyclopropanesulfonyl chloride (5.34mg, 0.038 mmol). The resulting mixture was stirred at rt for 3 h andthen heated at 30° C. overnight. DMAP (2.321 mg, 0.019 mmol) was added.The mixture was heated at 50° C. for 2 h before being allowed to cooldown and quenched with water. It was concentrated. The residue wasco-evaporated with toluene and chromatographed (silica, DCM/MeOH) toafford the title compound as yellow foam (4.7 mg, 44%). ESI MSm/z=533.10, 535.10 [M+H]⁺.

¹H NMR showed it was a mixture of 2 diastereomers, dr˜3/2.

Example 3

The title compound was obtained by chiral HPLC separation of Example 2with Chiralpak OD-H column (eluting with 30% i-PrOH in hexanes). ESI MSm/z=533.10, 535.10 [M+H]⁺.

Alternative Route for the Preparation of Example 3

Step 3a. To a suspension of Intermediate 1 (3.00 g, 5.30 mmol) and ethyl2-((diphenylmethylene)amino)acetate (1.985 g, 7.42 mmol) in toluene (54ml) cooled at 0° C. was addedO-Allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (0.321 g, 0.530mmol), followed by 50% KOH aq (17.68 ml, 265 mmol) dropwise. The mixturewas vigorously stirred at 0° C. for 2 h before being diluted withsaturated NaHCO₃ aq and MTBE. The organic layer was washed withsaturated NaHCO₃ aq (*1), brine (*1), dried over Na₂SO₄ (s), filteredand concentrated. The residue was dried under vacuum to afford thedesired compound as yellow foam (5.40 g), which was used directly fornext step. ESI MS m/z=751.14, 753.14 [M+H]⁺.

Step 3b. A clear orange solution of the compound from step 3a (5.40 g,5.30 mmol) in THF (30 ml), Water (30.00 ml) and AcOH (20.00 ml) wasstirred at rt for 2.5 h before being concentrated. The residue wasco-evaporated with DCM and some Et₃N (*1). It was purified by flashcolumn chromatography (silica, hexanes/EtOAc) to afford the desiredcompound as yellow foam (2.540 g, 82% over 2 steps). ESI MS m/z=587.06,589.06 [M+H]⁺. ¹H NMR showed the dr was ˜5/1.

Step 3c. To a clear yellow solution of the compound from step 3b (0.500g, 0.851 mmol) in DCM (10 ml) at rt was added DMAP (0.208 g, 1.701mmol), followed by Cbz-C₁ (0.146 ml, 1.021 mmol). The solution wasstirred at rt for 3 h before being quenched with saturated NaHCO₃ aq.and diluted with EtOAc and water. The organic layer was washed withbrine (*1), dried over Na₂SO₄ (s), filtered and concentrated. Theresidue was purified by flash column chromatography (silica,hexanes/EtOAc) to afford the desired compound as yellow solid (0.284 g,46%). ESI MS m/z=721.11, 723.11 [M+H]⁺.

Step 3d. To a solution of the compound from step 3c (0.284 g, 0.393mmol) and 1-methyl-3-(tributylstannyl)-1H-pyrazole (0.190 g, 0.511 mmol)in toluene (8 ml) at rt was added Pd(Ph₃P)₄ (68.2 mg, 0.059 mmol). Themixture was degassed 3 times before being heated at 135° C. using amicrowave reactor for 45 min. The mixture was directly purified by flashcolumn chromatography (silica, hexanes/EtOAc) to afford the desiredcompound as yellow oil (0.240 g, 84%). ESI MS m/z=723.24, 725.24 [M+H]⁺.

Step 3e. A solution of the compound from step 3d (0.240 g, 0.332 mmol)in DCM (4 ml) and TFA (2.000 ml) was stirred at rt for 1 h. The mixturewas concentrated. The residue was co-evaporated with toluene (*1), andthen DCM with some Et₃N (*1). The residue was purified by flash columnchromatography (silica, hexanes/EtOAc) to afford the desired compound asyellow solid (0.195 g, 94%). ESI MS m/z=623.18, 625.17 [M+H]⁺.

Step 3f. To a solution of the compound from step 3e (0.195 g, 0.313mmol) in THF (6 ml) at rt was added LiBH₄ (1.0 M in THF, 0.939 ml, 0.939mmol). The mixture was stirred at rt for 4.5 h. 1.0 N HCl solution wasadded dropwise until no bubble was observed. Excess tri-amine was added.The mixture was stirred at rt for 10 min before being diluted with EtOAcand saturated NH₄Cl aq. The organic layer was washed with brine (*1),dried over Na₂SO₄ (s), filtered and concentrated. The residue waspurified by flash column chromatography (silica, hexanes/EtOAc) toafford the desired compound as yellow foam (0.165 g, 91%). ESI MSm/z=581.16, 583.16 [M+H]⁺.

Step 3 g. To a yellow solution of the compound from step 3f (0.145 g,0.250 mmol) in DCM (5 ml) cooled at 0° C. was added Et₃N (0.070 ml,0.499 mmol), followed by a solution of MsCl (0.029 ml, 0.374 mmol) inDCM (0.1 ml). The resulting mixture was stirred at 0° C. for 1 h beforebeing diluted with DCM and water. The aqueous layer was extracted withDCM (*2). The combined organic layers were dried over Na₂SO₄ (s),filtered and concentrated. The residue was taken up in DCM (5 ml). Et₃N(0.070 ml, 0.500 mmol) was added. The mixture was stirred at 40° C. for6 h. The mixture was directly purified by flash column chromatography(silica, hexanes/EtOAc) to afford the desired compound as yellow foam(0.124 g, 88%). ESI MS m/z=563.15, 565.14 [M+H]⁺.

Step 3h. The compound from step 3 g (2.420 g, 4.30 mmol) was treatedwith 30% HBr in acetic acid (15.56 ml, 86 mmol) at rt for 1 h. Themixture was freed of volatile by rotavapor. The residue oil wastriturated with hexane/DCM (˜2/1, *2). The residue oil was dissolved inMeOH and poured into excess 7 M NH₃ in MeOH at 0° C. The resulting clearsolution was stirred at 0° C. for 15 min and then concentrated. Theresidue was partitioned between DCM and water. The aqueous layer wasextracted with DCM (*2). The combined organic layers were dried overNa₂SO₄ (s), filtered and concentrated. The residue was purified by flashcolumn chromatography (silica, hexanes/EtOAc) to afford the desiredmajor diasteromer as yellow foam (1.410 g, 76%). ESI MS m/z=429.10,431.09 [M+H]⁺.

Step 3i. To a yellow solution of the compound from step 3h (26.1 mg,0.061 mmol) in DCM (2 ml) at rt was added DMAP (14.87 mg, 0.122 mmol),followed by a solution of cyclopropanesulfonyl chloride (9.30 μl, 0.091mmol) in DCM (0.1 ml). The solution was stirred at rt for 3 h beforebeing quenched with excess i-PrOH at rt. The mixture was concentrated.The residue was purified by flash column chromatography (silica,hexanes/EtOAc) to afford the title compound as yellow foam (26.3 mg,81%). ESI MS m/z=533.10, 535.10 [M+H]⁺.

Example 4

Step 4a. To a suspension of Intermediate 2 (0.945 g, 1.733 mmol) andethyl 2-((diphenylmethylene)amino)acetate (0.927 g, 3.47 mmol) intoluene (17 ml) cooled at 0° C. was addedO-Allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (0.105 g, 0.173mmol), followed by 50% KOH aq (5.78 ml, 87 mmol) dropwise. The mixturewas vigorously stirred at 0° C. for 2 h before being diluted withsaturated NaHCO₃ aq and MTBE. The organic layer was washed withsaturated NaHCO₃ aq (*1), brine (*1), dried over Na₂SO₄ (s), filteredand concentrated. The residue was dried under vacuum to afford thedesired compound as yellow foam (1.830 g), which was used directly fornext step. ESI MS m/z=731.17, 733.17 [M+H]⁺.

Step 4b. A clear orange solution of the compound from step 4a (1.268 g,1.733 mmol) in THF (9 ml), Water (9.00 ml) and AcOH (6.00 ml) wasstirred at rt for 4 h before being concentrated. The residue was takenup in DCM and saturated NaHCO₃ aq. The aqueous layer was extracted withDCM (*1). The combine organic layers were dried over Na₂SO₄ (s),filtered and concentrated. The residue was purified by flash columnchromatography (silica, hexanes/EtOAc) to afford the desired compound asyellow foam (0.820 g, 83% over 2 steps). ESI MS m/z=567.11, 569.11[M+H]⁺.

Step 4c. To a clear yellow solution of the compound from step 4b (50.0mg, 0.088 mmol) in DCM (0.6 ml) was added 4 M HCl in 1,4-dioxane (0.551ml, 2.203 mmol) at rt. The resulting clear solution was stirred at rtfor 0.5 h before being freed of volatiles. The residue was dissolved inDCM and washed with saturated NaHCO₃ aq. The aqueous layer was extractedwith DCM (*1). The combine organic layers were dried over Na₂SO₄ (s),filtered and concentrated. The residue was dried under vacuum to affordthe desired compound as yellow foam (40.8 mg), which was used directlyfor next step. ESI MS m/z=467.05, 469.05 [M+H]⁺.

Step 4d. To a clear yellow solution of the compound from step 4c (40.8mg, 0.087 mmol) in DCM (2 ml) at rt was added DMAP (21.33 mg, 0.175mmol), followed by a solution of cyclopropanesulfonyl chloride (9.78 μl,0.096 mmol) in DCM (0.1 ml) dropwise. The solution was stirred at rt for3 h. Excess i-PrOH was added at rt to quench the reaction. After 5 min,the mixture was concentrated. The residue was purified by flash columnchromatography (silica, hexanes/EtOAc) to afford the desired compound asyellow foam (40.6 mg, 81%). ESI MS m/z=571.05, 573.05 [M+H]⁺.

Step 4e. To a solution of the compound from step 4d (40.6 mg, 0.071mmol) in THF (1 ml) at rt was added a solution of LiBH₄ in THF (1.0 M,0.213 ml, 0.213 mmol). The mixture was stirred at rt for 1.5 h. 0.5 NHCl solution was added dropwise until no bubble was observed. Excesstri-amine was added. The mixture was stirred at rt for 10 min beforebeing diluted with EtOAc and water. The organic layer was washed withbrine (*1), dried over Na₂SO₄ (s), filtered and concentrated. Theresidue was purified by flash column chromatography (silica,hexanes/EtOAc) to afford the desired compound as yellow foam (32.4 mg,86%). ESI MS m/z=529.04, 531.04 [M+H]⁺.

Step 4f. To a solution of the compound from step 4e (32.4 mg, 0.061mmol) in 1,2-dichloroethane (2 ml) at rt was added triethylamine (0.026ml, 0.184 mmol), followed by methanesulfonic anhydride (11.19 mg, 0.064mmol). The solution was stirred at 55° C. for 2 h. More methanesulfonicanhydride (11.19 mg, 0.064 mmol) was added. The solution was stirred at55° C. for 1.5 h before being allowed to cool down. Two drops of i-PrOHwas added at rt. The mixture was directly purified by flash columnchromatography (silica, hexanes/EtOAc) to afford the desired compound asyellow foam (27.4 mg, 88%). ESI MS m/z=511.03, 513.03 [M+H]⁺.

Step 4 g. To a solution of the compound from step 4f (27.4 mg, 0.054mmol) and 1-methyl-3-(tributylstannyl)-1H-pyrazole (25.9 mg, 0.070 mmol)in toluene (2 ml) at rt was added Pd(Ph₃P)₄ (9.29 mg, 8.04 μmol). Themixture was degassed 3 times before being heated at 135° C. using amicrowave reactor for 45 min. The mixture was directly purified by flashcolumn chromatography (silica, hexanes/EtOAc) to afford the titlecompound as yellow foam (19.2 mg, 70%). ESI MS m/z=513.15 [M+H]⁺.

Example 5

The title compound was obtained by chiral HPLC separation of Example 4with Chiralpak OD-H column (eluting with 10% i-PrOH in hexanes). ESI MSm/z=513.15 [M+H]⁺.

Example 6

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=507.08, 509.08 [M+H]⁺.

Example 7

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=521.10, 523.10 [M+H]⁺.

Example 8

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=535.12, 537.12 [M+H]⁺.

Example 9

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=583.12, 585.11 [M+H]⁺.

Example 10

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=547.12, 549.11 [M+H]⁺.

Example 11

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=547.11, 549.11 [M+H]⁺.

Example 12

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=579.10, 581.10 [M+H₂O+H]⁺.

Example 13

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=593.11, 595.11 [M+H₂O+H]⁺.

Example 14

The title compound was prepared following similar procedure as step 3i.ESI MS m/z=569.10, 571.10 [M+H]⁺.

Example 15

The title compound was prepared following similar procedure as thealternative route for the preparation of Example 3. ESI MS m/z=520.07,522.06 [M+H]⁺.

Example 16

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=531.14 [M+H]⁺.

Example 17

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=536.12, 538.11 [M+H]⁺.

Example 18

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=534.08, 536.08 [M+H]⁺.

Example 19

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=533.10, 535.10 [M+H]⁺.

Example 20

Step 20a. A solution of the compound from Step 3h (50.0 mg, 0.117 mmol)and sulfamide (33.6 mg, 0.350 mmol) in 1,4-dioxane (2 ml) was flushedwith N₂ and then heated at 110° C. in a sealed tube for 5 h. The mixturewas allowed to cool down and freed of volatiles with a stream of N₂. Theresidue was dissolved in DMSO (2 ml) and filtered. The filtrate wasdirectly purified by HPLC (40˜90% ACN in water) to afford the titlecompound as brown solid (42 mg, 72%). ESI MS m/z=508.07, 510.07 [M+H]⁺.

Example 21

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=534.08, 536.08 [M+H]⁺.

Example 22

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=547.11, 549.11 [M+H]⁺.

Example 23

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=530.09, 532.09 [M+H]⁺.

Example 24

The title compound was prepared following the similar procedure as thatof Example 5. ESI MS m/z=569.08, 571.08 [M+H]⁺.

Example 25

The title compound is prepared following the similar procedure as thatof Example 5.

Example 26

The title compound is prepared following the similar procedure as thatof Example 5.

Example 27

The title compound is prepared following the similar procedure as thatof Example 5.

Example 28

The title compound is prepared following the similar procedure as thatof Example 5.

Biological Activity

Methods: HepAD38 cells are maintained as previously reported (Ladner etal, Antimicrob. Agents Chemother. 1997, 4, 1715). Briefly, cells arepassaged upon attaining confluency in DMEM/F12 media in the presence of10% FBS, Penn/Strep, 250 μg/mL G418, and 1 μg/ml tetracycline. Novelcompounds are screened by first washing cells three times with PBS toremove tetracycline, and plating in 96 well plates at 35,000 cells/well.Compounds dissolved in DMSO are then diluted 1:200 into wells containingcells. Five days after compound addition, material is harvested foranalysis. For an extended 8 day analysis, cells are plated and treatedas described above, but media and compound are refreshed on d2 and d5post initial treatment.

On harvest day, virion DNA is obtained by lysing with Sidestep Lysis andStabilization Buffer and then quantified via quantitative real time PCR.Commercially available ELISA kits are used to quantitate the viralproteins HBsAg (Alpco) or HbeAg (US Biological) by following themanufacturer's recommended protocol after diluting samples to match thelinear range of their respective assays. Irrespective of readout,compound concentrations that reduce viral product accumulation in thecell lysates or supernatants by 50% relative to no drug controls (EC₅₀)are reported; EC₅₀ ranges are as follows: A<0.1 μM; B 0.1-1 μM; C>1 μM.

Compound toxicity is evaluated by seeding cells at 15,000 cells/well andtreating with compound as described above. Three days after compoundaddition, cells are treated with ATPLite reagent and compoundconcentrations that reduce total ATP levels in wells by 50% relative tono drug controls (CC₅₀) are reported; CC₅₀ ranges are as follows: A>25μM; B 10-25 μM; C<10 μM.

TABLE 1 Summary of Activities Compd. HepAD38 HepG2 Number EC₅₀ (μM) CC₅₀(μM)  1 A C  2 A A  3 A  4 A  5 A  6 A  7 A  8 A  9 A 10 A 11 A 12 A 13A 14 A 15 A 16 A 17 A A 18 A A 19 A 20 A A 21 A 22 A >6 23 B

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed:
 1. A method of treating an HBV infection in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound represented by Formula(IIIa), or a pharmaceutically acceptable salt thereof,

wherein A₁ is thiazolyl; B is hydrogen or methyl; X is optionallysubstituted phenyl; Y is optionally substituted phenyl or optionallysubstituted monocyclic heteroaryl; and

 is selected from the groups below,

wherein each of the above shown groups is optionally substituted; R₅ isselected from the group consisting of hydrogen, optionally substituted—C₁-C₈ alkyl, optionally substituted —C₂-C₈ alkenyl, optionallysubstituted —C₂-C₈ alkynyl, optionally substituted —C₃-C₈ cycloalkyl,optionally substituted 3- to 8-membered heterocyclic, optionallysubstituted aryl, optionally substituted heteroaryl, —C(O)R₁₁,—C(O)OR₁₁, —C(O)NR₁₁R₁₂, —S(O)₂R₁₁, —S(O)₂NR₁₁R₁₂; and R₁₁ and R₁₂ ateach occurrence are independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₈ alkyl, optionally substituted—C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl, optionallysubstituted —C₃-C₈ cycloalkyl, optionally substituted 3- to 8-memberedheterocyclic, optionally substituted aryl and optionally substitutedheteroaryl; alternatively, R₅ and R₁₁ are taken together with thenitrogen atom to which they are attached to form an optionallysubstituted 3- to 8-membered heterocyclic.
 2. The method of claim 1,wherein Y is selected from the following:

wherein each of the above shown groups is optionally substituted.
 3. Themethod of claim 1 wherein Y is selected from the groups below:

wherein R₂₀ is hydrogen, optionally substituted C₁-C₄-alkyl oroptionally substituted C₃-C₆-cycloalkyl.
 4. The method of claim 1wherein R₅ is selected from the groups set forth below:

wherein each of the above shown groups is optionally substituted whenpossible.
 5. The method of claim 1, wherein the compound of Formula(IIIa) is represented by Formula (IIIa-5) or Formula (IIIa-6),

or a pharmaceutically acceptable salt thereof, wherein X₁ is optionallysubstituted methyl, halo, CN, OR₁₁, or NR₁₁R₁₂; and m is 0, 1, 2, 3, 4or
 5. 6. The method of claim 5, wherein each X₁ is halo.
 7. The methodof claim 1, wherein the compound is selected from the compounds setforth below or a pharmaceutically acceptable salt thereof: CompoundStructure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28


8. The method of claim 1, further comprising administering to thesubject at least one additional therapeutic agent selected from thegroup consisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, literature-described capsidassembly modulator, reverse transcriptase inhibitor, TLR-agonist,inducer of cellular viral RNA sensor, and therapeutic vaccine.
 9. Themethod of claim 8, wherein the compound of Formula (I) and the at leastone additional therapeutic agent are co-formulated.
 10. The method ofclaim 8, wherein the compound of Formula (I) and the at least oneadditional therapeutic agent are co-administered.
 11. The method ofclaim 8, wherein the subject is refractory to at least one compoundselected from the group consisting of a HBV polymerase inhibitor,interferon, viral entry inhibitor, viral maturation inhibitor, distinctcapsid assembly modulator, inducer of cellular viral RNA sensor,therapeutic vaccine, antiviral compounds of distinct or unknownmechanism, and combination thereof.